A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy and Safety of AG10 in Subjects With Symptomatic Transthyretin Amyloid Cardiomyopathy (ATTRibute-CM Trial)
Trial Snapshot
- Phase
- Phase 3
- Status
- Completed
- Sponsor
- Enrollment
- 632
- Locations
- 103
- Primary Endpoint
- A Hierarchical Combination of All-Cause Mortality, Cumulative Frequency of CV-related Hospitalization, Change From Baseline in NT-proBNP and Change From Baseline in 6MWT at the Last Available Visit Where Both Subjects Had Non-missing Assessments.
Study Overview
Brief Summary
Phase 3 efficacy and safety study to evaluate acoramidis (AG10) HCl 800 mg administered orally twice a day compared to placebo in subjects with symptomatic Transthyretin Amyloid Cardiomyopathy (ATTR-CM).
Detailed Description
Transthyretin amyloid cardiomyopathy (ATTR-CM) is an underdiagnosed condition believed to affect more than 400,000 people worldwide. In ATTR-CM, the accumulation of transthyretin (TTR) amyloid results in thickening and stiffening of the heart, which often leads to heart failure or even death.
There are two forms of ATTR-CM:
- Wild Type* This form of the condition primarily develops in older individuals who do not carry gene mutations.
- Hereditary* This form of the condition comes from gene mutations passed down in families.
In this study we are researching the investigational drug acoramidis HCl 800 mg administered orally twice a day. Through the study, we want to evaluate the efficacy and safety of acoramidis in patients with ATTR-CM versus placebo.
This is a 30 month, randomized, double-blind, placebo-controlled study. This means that, during the 30 month study, investigators conducting the research and study participants will not know whether the study participant is receiving acoramidis or placebo.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- 18 Years to 90 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Have an established diagnosis of ATTR-CM with either wild-type TTR or variant TTR genotype
- •Have a history of heart failure evidenced by at least one prior hospitalization for heart failure or clinical evidence of heart failure without prior heart failure hospitalization manifested by signs or symptoms of volume overload or elevated intracardiac pressures or heart failure symptoms that required or require ongoing treatment with a diuretic.
- •New York Heart Association (NYHA) Class I-III symptoms due to ATTR cardiomyopathy.
- •On stable doses of cardiovascular medical therapy
- •Completed ≥150 m on the 6MWT on 2 tests that are within 15% of total distance walked prior to randomization
- •Biomarkers of myocardial wall stress, NT-proBNP level ≥300 pg/mL at screening
- •Have left ventricular wall (interventricular septum or left ventricular posterior wall) thickness ≥12 mm
Exclusion Criteria
- •Had acute myocardial infarction, acute coronary syndrome or coronary revascularization, or experienced stroke or transient ischemic attack within 90 days prior to screening
- •Has hemodynamic instability
- •Likely to undergo heart transplantation within a year of screening
- •Confirmed diagnosis of primary (light chain) amyloidosis
- •Biomarkers of myocardial wall stress, NT-proBNP level ≥8500 pg/mL at screening
- •Measure of kidney function, eGFR by MDRD formula <15 mL/min/1.73 m2
- •Current treatment with marketed drug products and other investigational agents for the treatment of ATTR-CM
- •Current treatment with calcium channel blockers with conduction system effects (e.g. verapamil, diltiazem). The use of dihydropyridine calcium channel blockers is allowed. The use of digitalis will only be allowed if required for management of atrial fibrillation with rapid ventricular response
Arms & Interventions
acoramidis HCl 800 mg
Subjects will receive acoramidis HCl 800 mg twice daily. 6MWT primary outcome will be assessed at the end of 12 months. The hierarchical combination of All-Cause mortality, cumulative frequency of cardiovascular-related hospitalizations, change from baseline in NT-proBNP levels, and change from baseline in distance walked on the 6MWT will be assessed after 30 months of treatment.
Intervention: acoramidis (Drug)
Placebo
Subjects will receive placebo to match twice daily. 6MWT primary outcome will be assessed at the end of 12 months. The hierarchical combination of All-Cause mortality, cumulative frequency of cardiovascular-related hospitalizations, change from baseline in NT-proBNP levels, and change from baseline in distance walked on the 6MWT will be assessed after 30 months of treatment.
Intervention: Placebo Oral Tablet (Drug)
Outcomes
Primary Outcomes
A Hierarchical Combination of All-Cause Mortality, Cumulative Frequency of CV-related Hospitalization, Change From Baseline in NT-proBNP and Change From Baseline in 6MWT at the Last Available Visit Where Both Subjects Had Non-missing Assessments.
Time Frame: Baseline up to Month 30
The endpoint was analyzed using Finkelstein-Schoenfeld method. The method combines all-cause mortality, cumulative frequency of CV-related hospitalizations, change from baseline in NT-proBNP and change from baseline in 6MWT in a hierarchical fashion. The method compares every participant with every other participant within strata, assigning a +1 to the "better" participant and a -1 to the "worse" participant and 0 if they are "tied". Participants who had heart transplantation or implantation of a cardiac mechanical assist device were handled in the same manner as death. 'Win' represents a participant doing better based on hierarchical comparison. The reported unit is the total percent of "wins" for each treatment group from performing such a hierarchical comparison across stratification factors in the study.
Secondary Outcomes
- Change From Baseline to Month 30 in the Distance Walked During the 6 Minute Walk Test (6MWT)(Month 30)
- Change From Baseline to Month 30 of the Kansas City Cardiomyopathy Questionnaire Overall Score (KCCQ-OS)(Month 30)
- Change From Baseline to Month 30 in Serum TTR (Prealbumin) Level(Month 30)
- All-cause Mortality by Month 30, Including Death Due to Any Cause, Heart Transplant or Cardiac Mechanical Assist Device (CMAD)(Baseline up to Month 30)